The cDNA of programmed cell death 1 (PD-1) was isolated in 1992 from a murine T cell hybridoma and a hematopoietic progenitor cell line undergoing apoptosis. Genetic ablation studies showed that deficiencies in PD-1 resulted in different autoimmune phenotypes in various mouse strains. PD-1-deficient allogeneic T cells with transgenic T cell receptors (TCRs) exhibited augmented responses to alloantigens, indicating that the PD-1 on T cells plays a negative regulatory role in response to antigen.
Several studies contributed to the discovery of the molecules that interact with PD-1. In 1999, the B7 homolog one (B7-H1, also called programmed death-ligand 1 [PD-L1]) was identified independently from PD-1 using molecular cloning and human expressed-sequence tag database searches based on its homology with B7 family molecules and it was shown that B7-H1 acts as an inhibitor of human T cell responses in vitro. These two independent lines of studies merged one year later when Freeman, Wood and Honjo's laboratories showed that B7-H1 (hereafter referred to as PD-L1) is a binding and functional partner of PD-1. Next it was determined that PD-L1-deficient mice (PD-L1 KO mice) were prone to the induction of autoimmune diseases although this strain of mice did not spontaneously develop such diseases. It becomes clear later that the PD-L1/PD-1 interaction plays a dominant role in the suppression of T cell responses in vivo, especially in the tumor microenvironment.
The instant initial study showed that tumor-associated PD-L1 facilitates apoptosis of activated T cells (Dong H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nature medicine. 2002; 8(8):793-800) and also stimulates IL-10 production in human peripheral blood T cells (Dong H, et al., B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature medicine. 1999; 5(12):1365-9) to mediate immune suppression. It is now known that the effects of PD-L1 on immune suppression are far more complicated. In addition to T cell apoptosis and IL-10 induction, PD-L1 can also induce T cell dysfunction through a variety of mechanisms. The PD pathway was also shown to promote T cell anergy in vitro and in vivo.
Recently, the FDA approved two PD-1 mAbs to treat human cancers, one from Bristol-Myers Squibb (Opdivo, nivolumab, MDX-1106, BMS-936558, ONO-4538) and the other from Merck (Keytruda, pembrolizumab, lambrolizumab, MK-3475). Additionally, multiple mAbs to either PD-1 or PD-L1 are under active development in hundreds of clinical trials involving thousands of patients. Thus far, anti-PD therapy generates significant clinical benefits by inducing regression of advanced and metastatic tumors and improved survival. More importantly, anti-PD therapy can have durable effects, tolerable toxicity, and show to be applicable to a broad spectrum of cancer types, especially in solid tumors. These clinical findings further validate the principles of the PD pathway blockade and put anti-PD therapy in a unique category distinct from personized or tumor type-specific therapy. Due to its distinct and non-overlapping mechanism with other cancer therapies, anti-PD therapy is on the way to combine with nearly all cancer treatment methods in an attempt to further amplify therapeutic efficacy. In addition to the combination with various cancer immunotherapy approaches such as cancer vaccine, costimulation and coinhibition antibody and adoptive cell therapy, various clinical trials are also initiated to combine anti-PD therapy with chemotherapy, radiotherapy and targeted therapy.
Anti-PD therapy has taken center stage in immunotherapies against human cancer, especially for solid tumors. This therapy is distinct from the prior immune therapeutic agents which largely aim to boost systemic immune responses or to generate de novo immunity against cancer; instead, anti-PD therapy modulates immune responses at the tumor site, targets tumor-induced immune defects, and repairs ongoing immune responses. While the clinical success of anti-PD therapy for the treatment of a variety of human cancers has validated this approach, we are still learning from this pathway and the associated immune responses, which will aid in the discovery and design of new clinically applicable approaches in cancer immunotherapy.